Typhoid and Non-Typhoidal Salmonellosis (NTS) are systemic diseases that annually cause 1 million global deaths. Given the impact of these infections on infants, the elderly, and immune suppressed individudals, a safe and effective sub-unit vaccine could have an enormous impact on this disease. While significant gains have been made in identifying the Salmonella target antigens recognized by systemic immune responses, we still know almost nothing about the target antigens recognized by tissue resident lymphocytes, a population that we now know is critical for the protective efficacy of live Salmonella vaccines. This application will focus on protective tissue resident memory (TRM) Th1 cells elicited by a protective live Salmonella vaccine and identify protective target antigens recognized by these cells. Our experimental approach is unique in that it will use natural water contamination challenge, a mouse model where CD4 TRM Th1 cells actively participate in protective immunity, and a set of tools that allow direct visualization of Salmonella-specific CD4 T cells. Our application specifically proposes to, (i) determine the role of tissue-resident memory T cells in the elimination of persistent Salmonella, (ii) uncover the unique TRM T cell receptors that allow greater protection against Salmonella infection, and (iii) identify the antigens recognized by this T cell subset and determine whether they can improve the effectiveness of a sub-unit vaccine for Salmonella.